Bottom Line:
Genes preferentially expressed in the placenta are predicted to evolve rapidly, and Tnfrh1 appears to be an example of this phenomenon.In view of its strong expression in cells at the fetal-maternal boundary, Tnfrh1 warrants further study as a gene that might modulate immune or trophic interactions between the invasive placental trophoblast and the maternal decidua.The preferential expression of Tnfrh1 from the maternal allele indicates weak functional imprinting of this locus in some tissues.

Affiliation: Institute for Cancer Genetics, Columbia University College of Physicians and Surgeons, New York, NY, USA. lc654@columbia.edu

ABSTRACT

Background: The Tnfrh1 gene (gene symbol Tnfrsf23) is located near one end of a megabase-scale imprinted region on mouse distal chromosome 7, about 350 kb distant from the nearest known imprinting control element. Within 20 kb of Tnfrh1 is a related gene called Tnfrh2 (Tnfrsf22) These duplicated genes encode putative decoy receptors in the tumor necrosis factor (TNF) receptor family. Although other genes in this chromosomal region show conserved synteny with genes on human Chr11p15.5, there are no obvious human orthologues of Tnfrh1 or Tnfrh2.

Results: We analyzed Tnfrh1 for evidence of parental imprinting, and characterized its tissue-specific expression. Tnfrh1 mRNA is detectable in multiple adult and fetal tissues, with highest expression in placenta, where in situ hybridization reveals a distinctive population of Tnfrh1-positive cells in maternal decidua, directly beneath the trophoblast giant cells. In offspring of interspecific mouse crosses, Tnfrh1 shows a consistent parent-of-origin-dependent allelic expression bias, with relative repression, but not silencing, of the paternal allele in several organs including fetal liver and adult spleen.

Conclusions: Genes preferentially expressed in the placenta are predicted to evolve rapidly, and Tnfrh1 appears to be an example of this phenomenon. In view of its strong expression in cells at the fetal-maternal boundary, Tnfrh1 warrants further study as a gene that might modulate immune or trophic interactions between the invasive placental trophoblast and the maternal decidua. The preferential expression of Tnfrh1 from the maternal allele indicates weak functional imprinting of this locus in some tissues.

Figure 6: Expression of Tnfrh1 is restricted to a discrete sub-population of cells near the fetal-maternal boundary.A, low-magnification image of 10.5 dpc placenta subjected to ISH with the Tnfrh1-antisense probe, showing a band of Tnfrh1-positive cells near the fetal-maternal junction. Signal in other areas is not higher than that seen with the sense control probe (not shown). Fe=fetal side of placenta, Ma=maternal side. B, the same section stained with hematoxylin-eosin (HE) to show cellular morphology. The arrows indicate trophoblast giant cells at the fetal-maternal boundary. The in situ image has been superimposed on the HE image, revealing Tnfrh1-positive cells restricted to the zone immediately under the trophoblast giant cells. C, superimposed ISH and HE images obtained from a placenta at 12.5 dpc, showing a distribution of Tnfrh1-positive cells similar to that at the earlier stage. Trophoblast giant cells are indicated by arrows. D, high-magnification field of another section at 12.5 dpc, which was first subjected to ISH and then lightly counterstained with periodic acid Schiff (PAS). The ISH reaction product persists under these conditions, revealing Tnfrh1-positive cells in close proximity to trophoblast giant cells.

Mentions:
To determine whether Tnfrh1 is expressed in the deep fetal component or, alternatively, in the maternal component of the placenta, we next carried out in situ hybridization with a digoxigenin-labeled Tnfrh1 cDNA probe. As shown in Figure 6a,6b,6c, this gave a detectable signal only in a narrow band of cells, situated immediately deep to the trophoblast giant cell layer. This restricted distribution of Tnfrh1-positive cells was observed both at 10.5 dpc, when the definitive placental layers have recently formed, and at 12.5 dpc, after these layers have begun to mature (Fig.6a,6b,6c). At high magnification, the Tnfrh1-positive cells were seen closely juxtaposed to trophoblast giant cells (Fig.6d). The morphology of these cells, and their location deep to the giant cell layer, suggested decidual parenchyma. These cells did not coincide with PAS-positive granulated uterine natural killer lymphocytes, or with CD3-positive infiltrating T-lymphocytes (data not shown). However, additional characterization will be necessary for a definitive assignment of cell type.

Figure 6: Expression of Tnfrh1 is restricted to a discrete sub-population of cells near the fetal-maternal boundary.A, low-magnification image of 10.5 dpc placenta subjected to ISH with the Tnfrh1-antisense probe, showing a band of Tnfrh1-positive cells near the fetal-maternal junction. Signal in other areas is not higher than that seen with the sense control probe (not shown). Fe=fetal side of placenta, Ma=maternal side. B, the same section stained with hematoxylin-eosin (HE) to show cellular morphology. The arrows indicate trophoblast giant cells at the fetal-maternal boundary. The in situ image has been superimposed on the HE image, revealing Tnfrh1-positive cells restricted to the zone immediately under the trophoblast giant cells. C, superimposed ISH and HE images obtained from a placenta at 12.5 dpc, showing a distribution of Tnfrh1-positive cells similar to that at the earlier stage. Trophoblast giant cells are indicated by arrows. D, high-magnification field of another section at 12.5 dpc, which was first subjected to ISH and then lightly counterstained with periodic acid Schiff (PAS). The ISH reaction product persists under these conditions, revealing Tnfrh1-positive cells in close proximity to trophoblast giant cells.

Mentions:
To determine whether Tnfrh1 is expressed in the deep fetal component or, alternatively, in the maternal component of the placenta, we next carried out in situ hybridization with a digoxigenin-labeled Tnfrh1 cDNA probe. As shown in Figure 6a,6b,6c, this gave a detectable signal only in a narrow band of cells, situated immediately deep to the trophoblast giant cell layer. This restricted distribution of Tnfrh1-positive cells was observed both at 10.5 dpc, when the definitive placental layers have recently formed, and at 12.5 dpc, after these layers have begun to mature (Fig.6a,6b,6c). At high magnification, the Tnfrh1-positive cells were seen closely juxtaposed to trophoblast giant cells (Fig.6d). The morphology of these cells, and their location deep to the giant cell layer, suggested decidual parenchyma. These cells did not coincide with PAS-positive granulated uterine natural killer lymphocytes, or with CD3-positive infiltrating T-lymphocytes (data not shown). However, additional characterization will be necessary for a definitive assignment of cell type.

Bottom Line:
Genes preferentially expressed in the placenta are predicted to evolve rapidly, and Tnfrh1 appears to be an example of this phenomenon.In view of its strong expression in cells at the fetal-maternal boundary, Tnfrh1 warrants further study as a gene that might modulate immune or trophic interactions between the invasive placental trophoblast and the maternal decidua.The preferential expression of Tnfrh1 from the maternal allele indicates weak functional imprinting of this locus in some tissues.

Affiliation:
Institute for Cancer Genetics, Columbia University College of Physicians and Surgeons, New York, NY, USA. lc654@columbia.edu

ABSTRACT

Background: The Tnfrh1 gene (gene symbol Tnfrsf23) is located near one end of a megabase-scale imprinted region on mouse distal chromosome 7, about 350 kb distant from the nearest known imprinting control element. Within 20 kb of Tnfrh1 is a related gene called Tnfrh2 (Tnfrsf22) These duplicated genes encode putative decoy receptors in the tumor necrosis factor (TNF) receptor family. Although other genes in this chromosomal region show conserved synteny with genes on human Chr11p15.5, there are no obvious human orthologues of Tnfrh1 or Tnfrh2.

Results: We analyzed Tnfrh1 for evidence of parental imprinting, and characterized its tissue-specific expression. Tnfrh1 mRNA is detectable in multiple adult and fetal tissues, with highest expression in placenta, where in situ hybridization reveals a distinctive population of Tnfrh1-positive cells in maternal decidua, directly beneath the trophoblast giant cells. In offspring of interspecific mouse crosses, Tnfrh1 shows a consistent parent-of-origin-dependent allelic expression bias, with relative repression, but not silencing, of the paternal allele in several organs including fetal liver and adult spleen.

Conclusions: Genes preferentially expressed in the placenta are predicted to evolve rapidly, and Tnfrh1 appears to be an example of this phenomenon. In view of its strong expression in cells at the fetal-maternal boundary, Tnfrh1 warrants further study as a gene that might modulate immune or trophic interactions between the invasive placental trophoblast and the maternal decidua. The preferential expression of Tnfrh1 from the maternal allele indicates weak functional imprinting of this locus in some tissues.